Case studies on Established Conditions 1 Established Conditions - - PowerPoint PPT Presentation

Joint BWP/QWP/GMDP IWG – Industry European Workshop on Lifecycle Management

Case studies on Established Conditions

1

Established Conditions (EC)

• EC for Manufacture and Control are binding information or

elements in the dossier concerning the manufacture and control of a pharmaceutical product

– Description of the product, elements of the manufacturing process, facilities and certain equipment, specifications and other elements of the associated control strategy

• EC may vary in their level of detail based on a sponsor’s

product and/or process understanding, ease of characterization and/or risks tied to product quality and performance

– E.g. Established Conditions, in certain cases, could simply be the method principle and the performance characteristics of a monitoring

• r testing method

Benefits

• Greater transparency within an organization and with

regulatory authorities

• Greater focus on mitigation of high risk elements
• Opportunities to utilize more effective and efficient post-

approval change management strategies

• Increased opportunities to provide supportive information
• Significant incentive to invest in the development of their

pharmaceutical products and their pharmaceutical quality system (PQS)

• Facilitation of continual improvement and seeking out
• pportunities for technical advancement

Majority of changes moved to “Do & Tell”

Manufacturing Process Description Possible Established Condition / Regulatory commitments Step 2

Established Condition (e.g. Critical Parameters, IPCs)

NOT Established Condition (e.g. Non-Critical Parameters)

Science and risk based development & Control Strategy Moderate/ high risk items.. Changes notified through regional

• requirements. Controlled

within PQS

PACMP

Modified “tell and do” / “do and tell.” Controlled within the PQS Low risk items Changes captured in the PQS Controlled within the PQS

“ “ Tel ell & Do ”

• ”

PAS, CBE, Type II, Type 1B

” D Do & & Tell ll “

Annual report, Type 1A, (Biologics IB/ IA possible?) (immediate or annual)

” D Do & & reco cord“ d“

PQS & APR only Not described in module 3

Low risk items Changes captured in the PQS Controlled within the PQS

Described in module 3

” D ” Do &

• & rep

eport“

PQS & Annual Report Supportive Information Not Established conditions Maintained in Knowledge management system CMC Dossier content Step 1

Topic Areas

• Overview of established conditions vs. non-established conditions

– Specific examples – Reporting mechanism for changes established and non-established conditions

• How would this be different
• What benefits would it bring (less focus on minor issues for Reg & Industry, allow

improvements, stock outs reduced and clearer compliance commitment, optional aspects)

– Is the level of detail in the dossier too high causing unnecessary change (too many Type IAs)? – Does the level of detail need to be less or simplify administration significantly?

• Practicalities of dossier management

– How do we get a workable way to represent ECs and Module 3 that is consistent across ICH – Consistency for Module 3 to be used globally

• Issues within EU & International

– Reference country approval (Type IA is ok?)

• Keep RoW in mind for broader harmonisation

Background

• Many “details” are provided in regulatory dossier to enhance understanding of the

manufacturing process and/or control strategy. Maintenance of those “details” is a burden.

• Examples of a recent variations for a drug substance (small molecule):

– Change in starting material quantity: from 200-235 kg’ to ‘195-235kg’ – Use of lower concentration of NaOH leading to higher volume loaded into the reaction (stoichiometry respected) – Lower amount of class 2 solvent used (from ‘2200-5650 kg’ to ‘2000-5650 kg’) – Stirring time changed from ‘approximately 2 hours’ to ‘at least 1 hour’ based

• n process experience (completion of reaction)
• Agreement on established conditions (EC) (to be maintained proactively) and non-

established conditions (non-EC) should help to focus on change(s) with a potential quality impact. Non-EC would not be subject to proactive reporting to Health Authorities (HA) as stand alone.

• Similar principle applies to clinical trial applications as described in Directive

2001/20/EC.

Implementation of ICH Q12 in current EU regulatory framework

• EU variation regulation does not allow to waive reporting for indefinite period.
• Simplify Type IA for easy grouping and/ or update following EC modification
• Broaden the usage of Type IA to support more usage of this variation category

beyond administrative Update of Classification Guideline (Article 5 notification if appropriate)

• Recommendation for changes in non-EC parameters to submit at the next

CTD module update (similar principle to ‘editorial change’).

• Voluntary reporting may be desirable as non-EC changes may be required to be submitted in

non ICH regions and ICH country submission/approval may be considered as reference.

• General Type IA without condition to facilitate dossier update, allowing

grouping of all non-EC changes into one single submission.

• List with relevant updated sections of dossier
• Multiple submissions may still be required depending on the implementation of each

individual non-EC parameters

• Precise scope to be defined to avoid maintenance of all non-EC (for instance P83)

EC considerations

• Clear and unambiguous identification of established conditions (EC) and non-

established conditions (non-EC) in the dossier is critical.

• ICH Q12 should provide guidance and multiple examples on how to identify and

present the EC/non-EC in the dossier.

• Separate annex is proposed as an example based on draft FDA guidance

(Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products).

• Location: part of CTD Module 2 and/or 3 (tbd, e.g. QOS or 3.2.A), as all ICH regions

should apply the same rules. This is critical for Industry to have as much as possible one single set of EC and non-EC in all ICH regions.

• For the majority of modules, identification of EC/non-EC should not be
• problematic. Difficulties are mainly expected for S.2.2, S.2.3-S.4.2, P.3.3-P.5.2 or

3.2.A.1.

1st Example

Case Study: Drug Product Manufacturing

Focus on:

• Small molecule / Simple DP pharmaceutical form
• CTD module 3.2.P.3 with focus on 3.2.P.3.3
• Use of cross references to identify EC

Option of how EC could be presented

• When hyperlinks are used, EC should be clearly identifiable in the module

(link to a specific table or complete specific section).

• Applicant should ensure that hyperlinks are maintained throughout

complete lifecycle (e-CTD filing).

• No risk of divergent information between the module 3 and EC annex

Identification of Established Conditions using hyperlinks:

Example of 3.2.P.3 section from EC annex

2nd Example

Case Study: Raw Materials

• CTD Module section 3.2.S.2.3
• Applicable to chemical entities as well as biologics
• Regulatory challenges

Page 15

Current Challenges

Case Study: Raw Materials

• High administrative burden for HAs and MAHs due to submission of every

(minor) change in the control of raw materials

High level of detail required for initial application assessment No differentiation between critical and non-critical raw materials EU: for some changes same reporting categories for DS, starting materials, intermediates and reagents → same data requirements Criticality of control is different for e.g. starting materials, media for biotech processes

• vs. standard reagents

RM manufacturer/supplier

• ften slightly change RM

specifications Large number of (minor) changes with no impact on quality

Regulatory framework Regulatory burden

• By applying the tools of ICH Q12 regulatory binding information will be defined

more clearly in the quality part of the dossier

• Overall less regulatory burden for low impact changes in raw material controls

Potential Resolution

Definition of “Established Conditions”

Established Condition Quality control of „critical“ raw materials Definition based on risk assessment, process and product understanding Regulatory binding Change management via established reporting categoried or pre-approved PALMP Non-Established Condition Additional, supportive information Quality control control of „non-critical“ raw materials Definition based on risk assessment, process and product understanding Not regulatory binding Change management within PQS No proactive reporting - update of dossier at e.g. next change in Established Condition

Changes in Specification for Raw Materials Defined as “Non- critical” → “Non-established Condition”

Change Classification acc. to applied ICH Q12 tools EU classification

• acc. to current

procedure US classification

• acc. to current

procedure Canadian classification

• acc. to current

procedure JP classification

• acc. to current

procedure 1-Octanol Refractive index n 20/D 1.4291 – 1.4300 to 1.4285 – 1.4303 (slightly widened limit) Managed within PQS Type IB by default B.I.b.1 z) Change in specification parameters and/or limits of a reagent Annual report Notifiable change submission (annual report only if change within approved limits) PAA 2-Butanol Deletion of test parameter „Odor – alcoholic, irritating“ Managed within PQS Type IA B.I.b.1 d) Deletion of a non- significant specification parameter Annual report Annual report PAA 2- Butanol Residue on evaporation NMT 10 mg to NMT 9 mg (tightening of limit) Managed within PQS Type IA B.I.b.1 b) Tightening of specification limits Annual report Annual report Minor change notification

Changes in Specification for Raw Materials Defined as “Critical” → “Established Condition”

Change Classification

• acc. to applied

ICH Q12 tools EU classification acc. to current procedure US classification

• acc. to current

procedure Canadian classification

• acc. to current

procedure JP classification

• acc. to current

procedure Soy peptone Residue on ignition (sulfated ash) NMT 15% to NMT 14% No change to current reporting categories Type IA B.I.b.1 b) Tightening of specification limits Annual report Annual report Minor change notification Soy peptone Nitrogen content NLT 8.5% to NLT 8.0% No change to current reporting categories Type II B.I.b.1 g) Widening of approved specification limits for starting materials /intermediates which may have a significant impact in the overall quality or Type IB by default B.I.b.1 z) Change in specification parameters and/or limits

• f a reagent

CBE30 (in case animal derived) Notifiable change submission (annual report only if change within approved limits) PAA

3rd Example

Case Study: Biological Drug Substance

• Established conditions:

– identified and justified in QOS – Further supported by Module 3 data

• Change in EC:

– Reported in accordance to variation classification guideline

• Change in non-EC:

– Managed through lifecycle strategy, following risk based approach

CTD format

Module 2 Module 3 Describe and justify EC Detailed information Consolidated EC & lifecycle strategy in R section

Option on how to describe EC

z Sections including EC identified and justified in QOS

Consolidated list of Established Conditions in QOS appendix and 3.R

Process Step Analytical Procedure Type of Limit Limit Step 1 and 2 Cell viability Action limit Temperature Action limit pH Action limit Disolved oxygen Action limit Inoculation density Action limit Culture duration Action limit Step 3 Temperature Acceptance criterion 32.0-39.0°C Nutriment feed Action limit pH Acceptance criterion 6.5-7.5 Culture duration Acceptance criterion 14-21 days Dissolved oxygen Acceptance criterion 15-80% Step 4 Cell age at harvest Acceptance criterion 210 PDL Mycoplasma Acceptance criterion None detected General Viral Screening Assay Preharvest Cell Culture Fluids Acceptance criterion None detected Rodent Parvovirus of Cell Culture Fluids Acceptance criterion Negative Hold duration Acceptance criterion <120hours at 2- 8°C Endotoxins Action limit Bioburden Action limit

Non-CPP limits :

Non-EC

(limits presented in QOS and Module 3, but not included in consolidated EC table)

CPP limit: EC CQA or IPC tested with acceptance limit (EC) at appropriate step CQA or IPC tested with action limit

(non-EC) at

appropriate step Control of CQA, IPC, CPP and non-CPP : EC

Principles included in lifecycle strategy

Risk Level PQS Reporting category Post-Approval Lifecycle Management (PALM) PLAN Change in EC Change in non-EC Yes None (managed within quality system only) Reporting managed through PALM plan 1 Yes Reported at next module update or via a consolidated sequence 2 Yes “Do and Tell” Type IA / Annual report

• r IA IN / immediate notification

IN ACCORDANCE WITH VARIATION REGULATIONS Level 3 and 4 could be downgraded in accordance to APPROVED PROTOCOL

• r DESIGN SPACE

3 Yes “Tell and Do”: Type IB/CBE-30 4 Yes Type II/PAS

Changes to CPP and non-CPP

Change Input Change limit

Input Limit

Delete or replace Add widen tighten

CPP EC EC 4 3 4 2 Non-CPP EC Non-EC 3 2 2* 1

Risk Level Reporting category None (managed within quality system only) 1 Reported at next module update or via a consolidated sequence 2 “Do and Tell” Type IA / Annual report or IA IN / immediate notification 3 “Tell and Do”: Type IB/CBE-30 4 Type II/PAS

* Depending on magnitude of change, risk level may be upgraded, and may be downgraded through planned design space verification activity and/or linkage study

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Summary

Benefits

• Greater transparency within an organization and with

regulatory authorities

• Greater focus on mitigation of high risk elements
• Opportunities to utilize more effective and efficient post-

approval change management strategies

• Increased opportunities to provide supportive information
• Significant incentive to invest in the development of their

pharmaceutical products and their pharmaceutical quality system (PQS)

• Facilitation of continual improvement and seeking out
• pportunities for technical advancement

Discussion Points

• An update to classification guide may be needed

– To allow more use of Type IA (change of non-EC) – Simplify reporting of multiple non-EC changes within one Type IA (listing of changes)

• Are we currently adding too much detail in Module 3?

– Is this an issue if we simplify and reduce administrative burden to report?

• How to increase consistency of EC across regions?

– How much guidance within ICH Q12 possible? – More examples, lists, Q&As...? – Clarity in Risk Assessment for EC/non-EC cutoff?

• Introduction of EC concept could complicate dossier management?

– Maintenance of non-ECs, transparency of EC/non-ECs in CTD – What is an acceptable time point for updating non-EC information, at next EC change vs. annual reporting?

• Grey zone between assessment and inspection

– More change management oversight by Inspectors